In the field of clinical diagnostic tests, various substances, which may be used as an index of diagnosis of diseases, in a large number of samples should be measured rapidly and accurately, and a rapid and accurate feedback of the results should be given to a treating room. In particular, immunological measurement based on an antigen-antibody reaction is widely used to accurately quantify a trace amount of a substance to be analyzed. In this regard, as a method for improving a detection sensitivity or accuracy, a latex agglutination method using particles made of a synthetic polymer such as polystyrene (so-called latex), in which an antigen or antibody specific for a substance to be analyzed is carried on the surface of the particles, is known. The latex agglutination method is a method for rapidly measuring a substance to be analyzed, by visually or optically detecting a degree of latex-particle-agglutination caused by a reaction of the substance to be analyzed with the antigen or antibody immobilized on the latex particles.
Further, a sandwich method, using magnetic particles instead of the latex particles, by trapping a substance to be analyzed with a first antibody immobilized on the magnetic particles, washing the magnetic particles accumulated by a magnet to remove unreacted substances and the like (so-called B/F separation), and adding a second antibody labeled with a signal-generating substance such as an enzyme or a fluorescent agent to thereby perform the analysis, is also widely used.
Almost all substances to be analyzed, which are quantified utilizing an antigen-antibody reaction, are generally trace components contained in biological samples, and therefore, accuracy in a low concentration range is important. However, because there is a case where an abnormally high level of a substance to be measured is observed in accordance with the progress of a disease, a reagent capable of accurately measuring from a low concentration range to a high concentration range is desired in the field of clinical diagnostic tests.
In methods using latex particles including the latex agglutination method and the sandwich method, it is essential to immobilize an antigen or antibody on the surface of the latex particles, and a method of physically or chemically immobilizing the antigen or antibody on the surface is used. For example, a method of directly immobilizing the antigen or antibody on the latex particles by physical adsorption, or a method of binding the antigen or antibody to the latex particles by a covalent binding via a functional group located on the surface of the latex particles, for example, an amino group, a carboxyl group, a mercapto group, a hydroxyl group, an aldehyde group, an epoxy group, or the like, is used.
However, an amount of the antigen or antibody capable of being carried on the latex surface is limited in these physically or chemically binding methods, and therefore, there is a limit to a measuring range or a detection sensitivity when the latex agglutination method or the sandwich method is carried out. That is, the properties (for example, a surface charge, a rate of introduced functional group, a distribution of particle size, or the like) of latex particles per se are not uniform among different lots or manufacturers, and therefore, even if a procedure of binding the antigen or antibody to latex particles is uniform, the properties of the resulting antibody-bound latex particles are not uniform. For example, in the methods of physically or chemically binding an antigen or antibody to the latex surface, not all amount of the antigen or antibody bind to the latex, and the unbound antigen or antibody is removed by washing after the binding procedure, or the bound antigen or antibody is often peeled from the latex by centrifugation or dispersion. That is, a change in the amount of an antigen or antibody bound affects a measuring range or a detection sensitivity.
Further, as a new problem recently raised, samples which cause a nonspecific reaction have been sometimes observed, as shown in non-patent reference 1. When an antigen or antibody is bound to the surface of latex particles, the antigen or antibody is structurally denatured, and the nonspecific reaction is caused by “a substance which binds to the denatured portion” contained in the samples. Due to the nonspecific reaction, the reliability of measured values is lost, and an accurate diagnosis cannot be made. This problem would not be solved by individual examinations as to an antigen or antibody, or latex particles, and is very difficult to solve.    [non-patent reference 1] Rinsho Byori (The Japanese Journal of Clinical Pathology), August 2000, vol. 48, no. 8, p. 760-763